Tissue systems biology of immune dysregulation in aging by single cell spatial metabolomics

通过单细胞空间代谢组学研究衰老过程中免疫失调的组织系统生物学

• 批准号: 10647249
• 负责人: Ahmet F. Coskun
• 金额: $ 21.56万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647249
• 关键词: 3-Dimensional; Affinity; Age; Aging; Anatomy; Antibodies; Antibody Formation; B Cell Proliferation; B-Cell Activation; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Biochemical Pathway; Bioinformatics; Biomedical Engineering; Biometry; Biotechnology; CD4 Positive T Lymphocytes; Cell Aging; Cell Cycle Arrest; Cell Maturation; Cell secretion; Cells; Cellular Metabolic Process; Cellular biology; Chemicals; Cholesterol; Collaborations; Data; Defect; Deterioration; Dissociation; Elderly; Enzymes; Event; Exhibits; Fatty Acids; Fingerprint; Genes; Goals; Helper-Inducer T-Lymphocyte; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunoglobulin Somatic Hypermutation; Immunology; Impairment; Individual; Infection; Inflammation; Knowledge; Lipids; Location; Lymph Node Tissue; Lymphoid Cell; Lymphoid Tissue; Maps; Measures; Memory B-Lymphocyte; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Mission; Modeling; Molecular; Mutate; Neighborhoods; Organ; Pathologic; Pathway interactions; Phenotype; Phosphatidylethanolamine; Physiological; Plasma Cells; Play; Population; Proliferating; Proteomics; Protocols documentation; Public Health; Reaction; Regulation; Research; Resolution; Role; Specialized Center; Stromal Cells; Structure; Structure of germinal center of lymph node; Systems Biology; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Technology; Testing; Tissues; Tonsil; Vaccines; age group; age related; aged; cell type; experience; fatty acid oxidation; glucose metabolism; human tissue; innovation; insight; lipid metabolism; lymph nodes; lymphoid organ; metabolic abnormality assessment; metabolomics; network models; pathogen; programs; protein profiling; response; secondary lymphoid organ; senescence; small molecule; tool

The immune system changes with age and gradually leads to incompetent immune responses against pathogens. Immune cells experience senescence, an irreversible cell cycle arrest, and secrete senescence- associated secretory phenotype (SASP) factors, causing pathological alterations of spatial organization and cell types in the germinal centers (GCs) of lymphoid organs. GC structures are impaired in the elderly population, reducing antibody production in aging individuals. B cell immunometabolism is crucial to meet the energy needs of rapid proliferation, somatic hypermutation, and affinity-based selection in GCs. However, the coordination of metabolic pathways in T follicular helper cells (TFH) and GC B cells is still not clearly understood. There is a critical need to decipher the TFH-dependent B cell immunometabolism at the single cell level in GCs for identifying aging-associated molecular defects. Thus, this project will leverage the recently developed spatially resolved metabolic profiling framework (3D-SMF) that maps the CD4+ T cell and B cell subsets and their metabolic correlates in native lymphoid tissues. Our long-term goal is to generate single cell metabolic insights of TFH-dependent B cell development in GCs of elderly individuals compared to young ones. The goal of this project is to define spatially resolved B cell immunometabolism pixel-by-pixel in fixed human tonsil and lymph node tissues. We hypothesize that unique metabolic programs of cellular senescence and SASP factor diversity are regulated by lipid metabolism events, causing age-dependent unique immunity; and these programs are distinctively potent in subtypes of secondary lymphoid organs in younger aged groups compared to the older ones. The rationale for this hypothesis is based on the 3D-SMF data showing depletion and enrichment of fatty acids in GCs located in native tonsil tissues. The central hypothesis will be tested by pursuing two specific Aims. Aim 1 will provide a deeper understanding of the lipid-associated immunometabolism in TFH cells and B-cell subsets (naïve, GC B cells, and plasma cells) in human tonsil tissues. Aim 2 will define how the metabolic network modeling of TFH and B cell subtypes and overall cell composition differs in lymph nodes in comparison to tonsil tissues. To accomplish these Aims, 3D-SMF and multiplexed enzyme profiling will be used to analyze B cell immunometabolism using a metabolic network comparison of B cell subsets in native tonsils and lymph nodes. This project builds an interdisciplinary team integrating experts from single cell biotechnology, bioengineering, inflammation in aging, metabolic modeling, and bioinformatics. The proposed application is innovative because it uses cutting-edge technology to define spatial metabolomics and proteomics of tonsil and lymph node tissues without dissociation protocols and shifts from the traditional focus on isolating T cell and B cells from their native microenvironment to study immune defects in aging. This research is significant because it defines TFH-dependent B cell immunometabolism in lymphoid tissues to decipher single-cell metabolic fingerprints of immune dysregulation in aging.

免疫系统随着年龄的增长而变化，并逐渐导致不称职 病原体。免疫细胞具有感应，不可逆的细胞周期停滞和秘密感应 相关的秘密表型（SASP）因素，导致空间组织的病理改变和 淋巴器官生发中心（GC）中的细胞类型。 GC结构在较长的 人口，减少衰老个体的抗体产生。 B细胞免疫代谢对于满足 GCS中快速增殖，体细胞超成熟和基于亲和力的选择的能量需求。但是， T卵泡辅助细胞（TFH）和GC B细胞中代谢途径的协调仍然不清楚 理解。在单个细胞处破译依赖TFH依赖性的B细胞免疫代谢的迫切需要 GC中用于识别衰老相关的分子缺损的水平。那，这个项目将利用最近的 开发了映射CD4+ T细胞和B细胞的空间分辨的代谢分析框架（3D-SMF） 亚群及其代谢在天然淋巴组织中相关。我们的长期目标是生成单元 与年轻人相比 一个。该项目的目的是定义固定在固定像素的空间解决B细胞免疫代谢像素 人扁桃体和淋巴结组织。我们假设细胞感应的独特代谢程序 SASP因子多样性受脂质代谢事件的调节，从而导致年龄依赖性独特的免疫力。 这些程序在年轻群体的次级淋巴机构的亚型中具有明显的潜力 与较旧的相比。该假设的基本原理基于3D-SMF数据显示定义 以及位于天然扁桃体组织中的GC中的脂肪酸富集。中心假设将通过 追求两个具体的目标。 AIM 1将提供对脂质相关的更深入的了解 人类扁桃体的TFH细胞和B细胞（幼稚，GC B细胞和浆细胞）中的免疫代谢 组织。 AIM 2将定义TFH和B细胞亚型的代谢网络建模以及整体细胞 与扁桃体组织相比，淋巴结的组成差异。为了实现这些目标，3D-SMF和 多路复用酶分析将用于使用代谢网络分析B细胞免疫代谢 比较天然扁桃体和淋巴结中B细胞子集的比较。该项目建立了一个跨学科团队 整合来自单细胞生物技术，生物工程，衰老中的炎症，代谢建模的专家 和生物信息学。提出的应用程序是创新的，因为它使用尖端技术来定义 扁桃体和淋巴结组织的空间代谢组学和蛋白质组学没有解离方案和移位 从传统的重点从其天然微环境中分离出T细胞和B细胞的传统重点来研究免疫 衰老的缺陷。这项研究很重要，因为它定义了依赖TFH的B细胞免疫代谢 淋巴组织可解解衰老中免疫调节的单细胞代谢指纹。